The Experts below are selected from a list of 222 Experts worldwide ranked by ideXlab platform
Jette E Kristiansen - One of the best experts on this subject based on the ideXlab platform.
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Phenothiazines as a solution for multidrug resistant tuberculosis from the origin to present
International Microbiology, 2015Co-Authors: Jette E Kristiansen, Sujata G Dastidar, Shauroseni Palchoudhuri, Oliver Hendricks, Jorn B ChristensenAbstract:Historically, multiplicity of actions in synthetic compounds is a rule rather than exception. The science of non-antibiotics evolved in this background. From the antimalarial and antitrypanosomial dye methylene blue, chemically similar compounds, the Phenothiazines, were developed. The Phenothiazines were first recognised for their antipsychotic properties, but soon after their antimicrobial functions came to be known and then such compounds were designated as non-antibiotics. The emergence of highly drug-resistant bacteria had initiated an urgent need to search for novel affordable compounds. Several Phenothiazines awakened the interest among scientists to determine their antimycobacterial activity. Chlorpromazine, trifluoperazine, methdilazine and thioridazine were found to have distinct antitubercular action. Thioridazine took the lead as researchers repeatedly claimed its potentiality. Although thioridazine is known for its central nervous system and cardiotoxic side-effects, extensive and repeated in vitro and in vivo studies by several research groups revealed that a very small dose of thioridazine is required to kill tubercle bacilli inside macrophages in the lungs, where the bacteria try to remain and multiply silently. Such a small dose is devoid of its adverse side-effects. Recent studies have shown that the (–) thioridazine is a more active antimicrobial agent and devoid of the toxic side effects normally encountered. This review describes the possibilities of bringing down thioridazine and its (–) form to be combined with other antitubercular drugs to treat infections by drug-resistant strains of Mycobacterium tuberculosis and try to eradicate this deadly disease. [Int Microbiol 2015; 18(1):1-12]Keywords: Mycobacterium tuberculosis · phenotiazines · thioridazine · tuberculosis
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role of Phenothiazines and structurally similar compounds of plant origin in the fight against infections by drug resistant bacteria
The Journal of Antibiotics, 2013Co-Authors: Sujata G Dastidar, Jette E Kristiansen, Joseph Molnar, Leonard AmaralAbstract:Phenothiazines have their primary effects on the plasma membranes of prokaryotes and eukaryotes. Among the components of the prokaryotic plasma membrane affected are efflux pumps, their energy sources and energy providing enzymes, such as ATPase, and genes that regulate and code for the permeability aspect of a bacterium. The response of multidrug and extensively drug resistant tuberculosis to Phenothiazines shows an alternative therapy for the treatment of these dreaded diseases, which are claiming more and more lives every year throughout the world. Many Phenothiazines have shown synergistic activity with several antibiotics thereby lowering the doses of antibiotics administered to patients suffering from specific bacterial infections. Trimeprazine is synergistic with trimethoprim. Flupenthixol (Fp) has been found to be synergistic with penicillin and chlorpromazine (CPZ); in addition, some antibiotics are also synergistic. Along with the antibacterial action described in this review, many Phenothiazines possess plasmid curing activities, which render the bacterial carrier of the plasmid sensitive to antibiotics. Thus, simultaneous applications of a phenothiazine like TZ would not only act as an additional antibacterial agent but also would help to eliminate drug resistant plasmid from the infectious bacterial cells.
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Phenothiazines bacterial efflux pumps and targeting the macrophage for enhanced killing of intracellular xdrtb
in Vivo, 2010Co-Authors: Leonard Amaral, Ana Martins, Miguel Viveiros, Gabriella Spengler, Jette E Kristiansen, Joseph Molnar, Marta Martins, Liliana Rodrigues, Isabel Couto, Jorge RamosAbstract:Phenothiazines have their primary effects on the plasma membrane of prokaryotes and eukaryotes. Among the components of the prokaryotic plasma membrane affected are efflux pumps, their energy sources, energy providing enzymes such as ATPases, and genes that regulate and code for permeability aspects of the bacterium. The responses of multi-drug (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis to the neuroleptic phenothiazine thioridazine are reviewed. The information collated suggests that this phenothiazine has the potential to cure XDR and MDR tuberculosis infections, a potential that has been recently demonstrated by its ability to cure 10 patients who presented with XDR TB infections. The mechanism by which this phenothiazine produces the desired effects within the infected macrophage is also discussed. The development of antimicrobial agents for the therapy of infection began in the late 19th century with the pioneering work of the German scientist Paul Erhlich. The studies conducted by Erhlich demonstrated that the newly created dye the phenothiazine methylene blue had activity against infectious bacteria and parasites (1). Previously, Bodoni had shown that the dye when administered to humans caused them to become lethargic (2) and although this study was not noticed for over 40 years, a similar conclusion was reached by others with the use of a phenothiazine antihistamine (3). However, the neuroleptic properties of the antihistamine were weak and attention was now focused on the methylene blue itself. Interest in this dye continued primarily as a result of the work by Perkin who had created the first chemically synthesized dye mauve some 50 years earlier and because of its commercial value, caused many to focus on the creation of additional dyes (4). Among the many discoveries obtained with the study of methylene blue was the development of dyes that could stain living tissue- vital stains. Because these dyes were derived from the phenothiazine methylene blue and they also inhibited motility of parasites, Roehl, a student of Erhlich, developed a canary model for malarial infection with Plasmodium yoelii and successfully treated the infected canary with a phenothiazinium salt created by Schulemann in 1932 by a chemical process that altered the side chain of methylene
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Phenothiazines potential management of creutzfeldt jacob disease and its variants
International Journal of Antimicrobial Agents, 2001Co-Authors: Leonard Amaral, Jette E KristiansenAbstract:Abstract Creutzfeldt–Jakob disease acquired from bovines (nvCJD) has been responsible for nearly 100 deaths in the UK and thousands more may die in the years to come. New variant CJD (nvCJD) is incurable and although clinical diagnosis is becoming more precise, the diagnosis is only certain at autopsy. Phenothiazine derivatives inhibit production of prions, the disease causing agent, in cultured neuroblastoma cells, and an advanced case of nvCJD was recently brought to remission by the use of these agents in combination with an antimalarial. In this review we present direct and circumstantial evidence in support of a model describing the manner by which the intracellular antimicrobial activity of Phenothiazines might cause the destruction of intracellular prions.
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activity of Phenothiazines against antibiotic resistant mycobacterium tuberculosis a review supporting further studies that may elucidate the potential use of thioridazine as anti tuberculosis therapy
Journal of Antimicrobial Chemotherapy, 2001Co-Authors: Leonard Amaral, Miguel Viveiros, Jette E Kristiansen, Jorge AtouguiaAbstract:The in vitro and in vivo anti-mycobacterial activities of a number of phenothiazine compounds are reviewed. These compounds, normally employed for the management of psychosis, inhibit the growth in vitro of Mycobacterium tuberculosis at concentrations that are significantly greater than those that can safely be achieved in a patient harbouring these infections. Nevertheless, one of these Phenothiazines, chlorpromazine, is concentrated by human macrophages to 10‐100 times its concentration in plasma, and has activity against mycobacteria that have been phagocytosed by these cells. Phenothiazines have significant in vitro activity against susceptible, polydrug- and multidrug-resistant strains of M. tuberculosis, as well as enhancing the activity of some agents employed for first-line treatment. Because thioridazine, the very mild anti-psychotic agent whose most common side effect is drowsiness, has equal anti-tuberculosis properties in vitro to chlorpromazine, we recommend that thioridazine be studied as an adjuvant to the four- or five-drug regimens employed for the management of a freshly diagnosed tuberculosis infection of unknown antibiotic susceptibility, at least during the period required for the assessment of antibiotic susceptibility. Because it also enhances the activity of rifampicin and streptomycin, antibiotics that frequently have adverse effects, additional studies evaluating the use of thioridazine as an adjuvant may eventually allow a reduction in the dosages of these antibiotics and result in a decreased frequency of adverse effects. It is important to note that whereas the management of patients with thioridazine for periods in excess of many months will result in the appearance of some undesirable side effects, its use for a limited period of 2‐3 months should not produce side effects that are more severe than simple drowsiness. Nevertheless, further in vitro and in vivo studies are essential before thioridazine may be recommended for the management of select cases of pulmonary tuberculosis.
Leonard Amaral - One of the best experts on this subject based on the ideXlab platform.
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multidrug resistance reversing activity of newly developed Phenothiazines on p glycoprotein abcb1 related resistance of mouse t lymphoma cells
Anticancer Research, 2014Co-Authors: Gabriella Spengler, Daniella Takacs, Adam Horvath, Zsuzsanna Riedl, Gyorgy Hajos, Leonard Amaral, József MolnárAbstract:Background: Phenothiazines have anticancer properties and are able to reverse the multidrug resistance of neoplastic cells by inhibiting the ATP-binding cassette, sub-family B (MDR/TAP), member 1 protein (ABCB1 or Pglycoprotein) activity. Materials and Methods: A series of new phenothiazine derivatives was investigated regarding their ABCB1-modulating effect on multidrug resistant mouse T-lymphoma cells by rhodamine 123 accumulation assay and real-time ethidium bromide accumulation assay. Results: The phenothiazine derivatives exhibited a potent anticancer effect on the parental cell line and on its multidrug-resistant mouse T-lymphoma subline overexpressing the ABCB1 transporter. The inhibition of the ABCB1 transporter in the presence of the newly-developed Phenothiazines was greater than that for the known ABCB1 inhibitors thioridazine and verapamil. Conclusion: Based on the chemical structures and biological activity, compounds with bivalent sulfur atom in the phenothiazine ring demonstrated marked ABCB1-modulating effect, however, other derivatives with halogen or amide substitutions were ineffective.
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role of Phenothiazines and structurally similar compounds of plant origin in the fight against infections by drug resistant bacteria
The Journal of Antibiotics, 2013Co-Authors: Sujata G Dastidar, Jette E Kristiansen, Joseph Molnar, Leonard AmaralAbstract:Phenothiazines have their primary effects on the plasma membranes of prokaryotes and eukaryotes. Among the components of the prokaryotic plasma membrane affected are efflux pumps, their energy sources and energy providing enzymes, such as ATPase, and genes that regulate and code for the permeability aspect of a bacterium. The response of multidrug and extensively drug resistant tuberculosis to Phenothiazines shows an alternative therapy for the treatment of these dreaded diseases, which are claiming more and more lives every year throughout the world. Many Phenothiazines have shown synergistic activity with several antibiotics thereby lowering the doses of antibiotics administered to patients suffering from specific bacterial infections. Trimeprazine is synergistic with trimethoprim. Flupenthixol (Fp) has been found to be synergistic with penicillin and chlorpromazine (CPZ); in addition, some antibiotics are also synergistic. Along with the antibacterial action described in this review, many Phenothiazines possess plasmid curing activities, which render the bacterial carrier of the plasmid sensitive to antibiotics. Thus, simultaneous applications of a phenothiazine like TZ would not only act as an additional antibacterial agent but also would help to eliminate drug resistant plasmid from the infectious bacterial cells.
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Phenothiazines bacterial efflux pumps and targeting the macrophage for enhanced killing of intracellular xdrtb
in Vivo, 2010Co-Authors: Leonard Amaral, Ana Martins, Miguel Viveiros, Gabriella Spengler, Jette E Kristiansen, Joseph Molnar, Marta Martins, Liliana Rodrigues, Isabel Couto, Jorge RamosAbstract:Phenothiazines have their primary effects on the plasma membrane of prokaryotes and eukaryotes. Among the components of the prokaryotic plasma membrane affected are efflux pumps, their energy sources, energy providing enzymes such as ATPases, and genes that regulate and code for permeability aspects of the bacterium. The responses of multi-drug (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis to the neuroleptic phenothiazine thioridazine are reviewed. The information collated suggests that this phenothiazine has the potential to cure XDR and MDR tuberculosis infections, a potential that has been recently demonstrated by its ability to cure 10 patients who presented with XDR TB infections. The mechanism by which this phenothiazine produces the desired effects within the infected macrophage is also discussed. The development of antimicrobial agents for the therapy of infection began in the late 19th century with the pioneering work of the German scientist Paul Erhlich. The studies conducted by Erhlich demonstrated that the newly created dye the phenothiazine methylene blue had activity against infectious bacteria and parasites (1). Previously, Bodoni had shown that the dye when administered to humans caused them to become lethargic (2) and although this study was not noticed for over 40 years, a similar conclusion was reached by others with the use of a phenothiazine antihistamine (3). However, the neuroleptic properties of the antihistamine were weak and attention was now focused on the methylene blue itself. Interest in this dye continued primarily as a result of the work by Perkin who had created the first chemically synthesized dye mauve some 50 years earlier and because of its commercial value, caused many to focus on the creation of additional dyes (4). Among the many discoveries obtained with the study of methylene blue was the development of dyes that could stain living tissue- vital stains. Because these dyes were derived from the phenothiazine methylene blue and they also inhibited motility of parasites, Roehl, a student of Erhlich, developed a canary model for malarial infection with Plasmodium yoelii and successfully treated the infected canary with a phenothiazinium salt created by Schulemann in 1932 by a chemical process that altered the side chain of methylene
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Phenothiazines potential management of creutzfeldt jacob disease and its variants
International Journal of Antimicrobial Agents, 2001Co-Authors: Leonard Amaral, Jette E KristiansenAbstract:Abstract Creutzfeldt–Jakob disease acquired from bovines (nvCJD) has been responsible for nearly 100 deaths in the UK and thousands more may die in the years to come. New variant CJD (nvCJD) is incurable and although clinical diagnosis is becoming more precise, the diagnosis is only certain at autopsy. Phenothiazine derivatives inhibit production of prions, the disease causing agent, in cultured neuroblastoma cells, and an advanced case of nvCJD was recently brought to remission by the use of these agents in combination with an antimalarial. In this review we present direct and circumstantial evidence in support of a model describing the manner by which the intracellular antimicrobial activity of Phenothiazines might cause the destruction of intracellular prions.
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activity of Phenothiazines against antibiotic resistant mycobacterium tuberculosis a review supporting further studies that may elucidate the potential use of thioridazine as anti tuberculosis therapy
Journal of Antimicrobial Chemotherapy, 2001Co-Authors: Leonard Amaral, Miguel Viveiros, Jette E Kristiansen, Jorge AtouguiaAbstract:The in vitro and in vivo anti-mycobacterial activities of a number of phenothiazine compounds are reviewed. These compounds, normally employed for the management of psychosis, inhibit the growth in vitro of Mycobacterium tuberculosis at concentrations that are significantly greater than those that can safely be achieved in a patient harbouring these infections. Nevertheless, one of these Phenothiazines, chlorpromazine, is concentrated by human macrophages to 10‐100 times its concentration in plasma, and has activity against mycobacteria that have been phagocytosed by these cells. Phenothiazines have significant in vitro activity against susceptible, polydrug- and multidrug-resistant strains of M. tuberculosis, as well as enhancing the activity of some agents employed for first-line treatment. Because thioridazine, the very mild anti-psychotic agent whose most common side effect is drowsiness, has equal anti-tuberculosis properties in vitro to chlorpromazine, we recommend that thioridazine be studied as an adjuvant to the four- or five-drug regimens employed for the management of a freshly diagnosed tuberculosis infection of unknown antibiotic susceptibility, at least during the period required for the assessment of antibiotic susceptibility. Because it also enhances the activity of rifampicin and streptomycin, antibiotics that frequently have adverse effects, additional studies evaluating the use of thioridazine as an adjuvant may eventually allow a reduction in the dosages of these antibiotics and result in a decreased frequency of adverse effects. It is important to note that whereas the management of patients with thioridazine for periods in excess of many months will result in the appearance of some undesirable side effects, its use for a limited period of 2‐3 months should not produce side effects that are more severe than simple drowsiness. Nevertheless, further in vitro and in vivo studies are essential before thioridazine may be recommended for the management of select cases of pulmonary tuberculosis.
Kristina Viktorsson - One of the best experts on this subject based on the ideXlab platform.
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harnessing the lysosome dependent antitumor activity of Phenothiazines in human small cell lung cancer
Cell Death and Disease, 2017Co-Authors: D Zong, Katarzyna Zielinskachomej, Therese Juntti, Birgitta Mork, Rolf Lewensohn, Petra Haag, Kristina ViktorssonAbstract:Phenothiazines are a family of heterocyclic compounds whose clinical utility includes treatment of psychiatric disorders as well as chemotherapy-induced emesis. Various studies have demonstrated that these compounds possess cytotoxic activities in tumor cell lines of different origin. However, there is considerable confusion regarding the molecular basis of phenothiazine-induced cell death. Lung cancer (LC) remains one of the most prevalent and deadly malignancies worldwide despite considerable efforts in the development of treatment strategies, especially new targeted therapies. In this work, we evaluated the potential utility of Phenothiazines in human LC. We show that Phenothiazines as single treatment decreased cell viability and induced cell death preferentially in small cell lung carcinoma (SCLC) over non small cell lung carcinoma (NSCLC) cell lines. Sensitivity to Phenothiazines was not correlated with induction of apoptosis but due to phenothiazine-induced lysosomal dysfunction. Interestingly, the higher susceptibility of SCLC cells to phenothiazine-induced cell death correlated with an intrinsically lower buffer capacity in response to disruption of lysosomal homeostasis. Importantly, this effect in SCLC occurred despite mutation in p53 and was not influenced by intrinsic sensitivity/resistance toward conventional chemotherapeutic agents. Our data thus uncovered a novel context-dependent activity of Phenothiazines in SCLC and suggest that Phenothiazines could be considered as a treatment regimen of this disease, however, extended cell line analyses as well as in vivo studies are needed to make such conclusion.
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chemosensitization by Phenothiazines in human lung cancer cells impaired resolution of γh2ax and increased oxidative stress elicit apoptosis associated with lysosomal expansion and intense vacuolation
Cell Death and Disease, 2011Co-Authors: D Zong, Rolf Lewensohn, Petra Haag, I Yakymovych, Kristina ViktorssonAbstract:Chemotherapy resistance poses severe limitations on the efficacy of anti-cancer medications. Recently, the notion of using novel combinations of ‘old' drugs for new indications has garnered significant interest. The potential of using Phenothiazines as chemosensitizers has been suggested earlier but so far our understanding of their molecular targets remains scant. The current study was designed to better define phenothiazine-sensitive cellular processes in relation to chemosensitivity. We found that Phenothiazines shared the ability to delay γH2AX resolution in DNA-damaged human lung cancer cells. Accordingly, cells co-treated with chemotherapy and Phenothiazines underwent protracted cell-cycle arrest followed by checkpoint escape that led to abnormal mitoses, secondary arrest and/or a form of apoptosis associated with increased endogenous oxidative stress and intense vacuolation. We provide evidence implicating lysosomal dysfunction as a key component of cell death in phenothiazine co-treated cells, which also exhibited more typical hallmarks of apoptosis including the activation of both caspase-dependent and -independent pathways. Finally, we demonstrated that vacuolation in phenothiazine co-treated cells could be reduced by ROS scavengers or the vacuolar ATPase inhibitor bafilomycin, leading to increased cell viability. Our data highlight the potential benefit of using Phenothiazines as chemosensitizers in tumors that acquire molecular alterations rendering them insensitive to caspase-mediated apoptosis.
D Zong - One of the best experts on this subject based on the ideXlab platform.
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harnessing the lysosome dependent antitumor activity of Phenothiazines in human small cell lung cancer
Cell Death and Disease, 2017Co-Authors: D Zong, Katarzyna Zielinskachomej, Therese Juntti, Birgitta Mork, Rolf Lewensohn, Petra Haag, Kristina ViktorssonAbstract:Phenothiazines are a family of heterocyclic compounds whose clinical utility includes treatment of psychiatric disorders as well as chemotherapy-induced emesis. Various studies have demonstrated that these compounds possess cytotoxic activities in tumor cell lines of different origin. However, there is considerable confusion regarding the molecular basis of phenothiazine-induced cell death. Lung cancer (LC) remains one of the most prevalent and deadly malignancies worldwide despite considerable efforts in the development of treatment strategies, especially new targeted therapies. In this work, we evaluated the potential utility of Phenothiazines in human LC. We show that Phenothiazines as single treatment decreased cell viability and induced cell death preferentially in small cell lung carcinoma (SCLC) over non small cell lung carcinoma (NSCLC) cell lines. Sensitivity to Phenothiazines was not correlated with induction of apoptosis but due to phenothiazine-induced lysosomal dysfunction. Interestingly, the higher susceptibility of SCLC cells to phenothiazine-induced cell death correlated with an intrinsically lower buffer capacity in response to disruption of lysosomal homeostasis. Importantly, this effect in SCLC occurred despite mutation in p53 and was not influenced by intrinsic sensitivity/resistance toward conventional chemotherapeutic agents. Our data thus uncovered a novel context-dependent activity of Phenothiazines in SCLC and suggest that Phenothiazines could be considered as a treatment regimen of this disease, however, extended cell line analyses as well as in vivo studies are needed to make such conclusion.
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chemosensitization by Phenothiazines in human lung cancer cells impaired resolution of γh2ax and increased oxidative stress elicit apoptosis associated with lysosomal expansion and intense vacuolation
Cell Death and Disease, 2011Co-Authors: D Zong, Rolf Lewensohn, Petra Haag, I Yakymovych, Kristina ViktorssonAbstract:Chemotherapy resistance poses severe limitations on the efficacy of anti-cancer medications. Recently, the notion of using novel combinations of ‘old' drugs for new indications has garnered significant interest. The potential of using Phenothiazines as chemosensitizers has been suggested earlier but so far our understanding of their molecular targets remains scant. The current study was designed to better define phenothiazine-sensitive cellular processes in relation to chemosensitivity. We found that Phenothiazines shared the ability to delay γH2AX resolution in DNA-damaged human lung cancer cells. Accordingly, cells co-treated with chemotherapy and Phenothiazines underwent protracted cell-cycle arrest followed by checkpoint escape that led to abnormal mitoses, secondary arrest and/or a form of apoptosis associated with increased endogenous oxidative stress and intense vacuolation. We provide evidence implicating lysosomal dysfunction as a key component of cell death in phenothiazine co-treated cells, which also exhibited more typical hallmarks of apoptosis including the activation of both caspase-dependent and -independent pathways. Finally, we demonstrated that vacuolation in phenothiazine co-treated cells could be reduced by ROS scavengers or the vacuolar ATPase inhibitor bafilomycin, leading to increased cell viability. Our data highlight the potential benefit of using Phenothiazines as chemosensitizers in tumors that acquire molecular alterations rendering them insensitive to caspase-mediated apoptosis.
Noboru Motohashi - One of the best experts on this subject based on the ideXlab platform.
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Theoretical Studies on Phenothiazines, Benzo(a)Phenothiazines, and Benz(c)acridines
Topics in Heterocyclic Chemistry, 2008Co-Authors: Teruo Kurihara, Hiroshi Sakagami, Noboru Motohashi, Kazumi Shinohara, Makoto Inabe, Hidetsugu Wakabayashi, Joseph MolnarAbstract:Quantitative structure–activity relationship (QSAR) analysis for minimum inhibitory concentration (MIC) of Phenothiazines and benzo[a]Phenothiazines was investigated based on the theoretical calculations. Four different dipole moments (μ G, μ ESP−G, μ W, and μ ESP−W) and heats of formation (ΔH f) of the Phenothiazines [1–20], benzo [a]Phenothiazines [21–29], and benz[c]acridines [30–41] were separately calculated in the gas-phase and the water-solution by the conductor-like screening model/parametric method 3 (COSMO/PM3) technique. The MIC values of Phenothiazines [1–20] were well correlated to ΔΔH f, HOMO energy and μ G. QSAR may be applicable to predict the MIC of Phenothiazines.
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antibacterial activity of artificial Phenothiazines and isoflavones from plants
2008Co-Authors: Asish Dasgupta, Sujata G Dastidar, Yoshiaki Shirataki, Noboru MotohashiAbstract:Significant antimicrobial action was detected in vitro and in vivo in Phenothiazines that are applied to humans as neuroleptics or antihistamines. Both Gram-positive and Gram-negative bacteria were equally sensitive, with the MIC varying between 25 and 100 μg/ml with most agents. Some Phenothiazines were bactericidal, while others were bacteriostatic in action. Similar activity could be observed in isoflavonones obtained from the plants Sophora spp. Trifluoperazine and methdilazine exhibited antimycobacterial properties as well, and in experimental animals the latter showed definite healing properties. Chlorpromazine and thioridazine were able to eliminate R-plasmids in drug-resistant bacteria. Artificially synthesized Benzo[α]Phenothiazines could effectively suppress adenovirus oncogene expression. Phenothiazines have now been shown to inhibit efflux pumps in multidrug-resistant bacteria.
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cytotoxic potential of Phenothiazines
Current Drug Targets, 2006Co-Authors: Noboru Motohashi, Masami Kawase, Kazue Satoh, Hiroshi SakagamiAbstract:Phenothiazines, a kind of sulfur-containing tricyclic compounds, have diverse biological activities including tranquilizer, antibacterial, antitumor and antihelmintic activities due to the relatively lower cytotoxicity. Phenothiazines have been used for clinical treatments as psychotropics. In contrast to the psychotropic preparations, their information of other biological activities of Phenothiazines and their related compounds has been limited. This review article summarizes the interaction with DNA (using quantum calculation), antitumor activity, differentiation or apoptosis-inducing activity, tumor necrosis factor (TNF)-induction, antiproliferative activity, radical scavenging activity, antimutagenic activity, antiplasmid activity, antibacterial activity, reversal of multidrug resistance (MDR), blast transformation activity of Phenothiazines, benz[c]acridines and benzo[a]Phenothiazines.
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Antimicrobial activity of Phenothiazines, benzo[a]Phenothiazines and benz[c]acridines
Anticancer Research, 1992Co-Authors: Noboru Motohashi, Hiroshi Sakagami, T Kurihara, K Csuri, Lajos Ferenczy, József MolnárAbstract:The abilities of 14 Phenothiazines, 8 benzo[a]Phenothiazines and 12 benz[c]acridines to induce an antibacterial effect against Escherichia coli K12 were compared. Several Phenothiazines, which showed antiplasmid activity, displayed the most potent antibacterial activity. All benz[c]acridine derivatives were moderately antibacterial, whereas benzo[a]Phenothiazines were inactive. The active phenothiazine derivatives had more potent inhibitory activity against fungi, including phytopathogen flamentous, human pathogen filamentous fungi and yeasts, than against gram-positive and -negative becteria
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Antitumor Properties of Phenothiazines
Cancer Investigation, 1991Co-Authors: Noboru Motohashi, Sitaraghav R. Gollapudi, Jahangir Emrani, Kesava Rao BhattiproluAbstract:AbstractThe purpose of this review is to describe and evaluate the antineoplastic properties of Phenothiazines. The present research studies suggest that many Phenothiazines do not show significant antitumor and antineoplastic activity and so they cannot be used as potential drugs to treat cancer. However some of their derivatives help indirectly in decreasing cytotoxic effects caused by radiation and other chemical carcinogens. Additionally, some phenothiazine derivatives provide protection against cancers caused by metabolic activation of carcinogens such as dimethylbenzanthracene. The selective accumulation of phenothiazine derivatives in certain tissues such as brain and melanoma tumors may provide an effective treatment of such tumors. Current studies suggest that highly potent phenothiazine derivatives can be made by nitro substitution on the aromatic ring of Phenothiazines.
